This invention relates to certain cyclic enediyne compounds and their precursor compounds, both of which have DNA cleavage, protein degrading and/or modulating antimicrobial and cytotoxic (antitumor) properties. More particularly, the invention relates to C3-substituted cyclodeca-1,5-diyn-3-enes and (E)-C3-substituted-4-(aryl- or heteroarylmethylidene)cyclodeca-1,5diynes, processes for preparing such compounds including a novel allylic rearrangement for converting the latter compounds into the former compounds, pharmaceutical compositions containing such compounds and their use for cleaving DNA, degrading or modulating a protein, inhibiting tumor growth, inhibiting microbial growth and treating cancer.
The (Z)-hexa-1,5-diyn-3-ene moiety embedded in a 10-membered ring is highly strained but is a biologically important structural unit found in the naturally occurring enediyne antitumor antibiotics. See Nicolaou and Dai, Angew. Chem. Int. Ed. Engl., 30:1387 (1991). It is generally believed that the enediyne core found in the naturally occurring enediyne antitumor antibiotics, such as Calicheamicin xcex311, is bio-reductively activated and forms a 1,4-benzenoid diradical through cycloaromatization. The resultant radical species are reported to cause DNA strand scission by abstraction of hydrogen atom(s) from the sugar-phosphate backbone. Interaction of the carbon-centered radical with peptides and proteins has been reported. Cortazzo and Schor demonstrated enediyne-induced apoptosis in an article published in Cancer Res. 56:1199 (1996). Damage to histones by enediynes are also known in the literature [Zein et al., Chem. Biol. 2:451 (1995); Zein et al., Proc. Natl. Acad. Sci. U.S.A. 90:8009 (1993)]. Recently, Jones et al. demonstrated that peptide radicals are generated from the interaction with enediyne-derived diradical species in an article published in Org. Lett. 2:811 (2000). Reactive enediynes capable of generating a 1,4-benzenoid diradical through cycloaromatization are therefore useful compounds for biomedical applications.
Synthesis of the 10-membered ring enediynes is a challenging undertaking in organic synthesis because of the high strain energy associated with the bent acetylene units. The parent cyclodeca-1,5-diyn-3-ene was first synthesized, albeit in low yield, via a Ramberg-Bxc3xa4cklund reaction using KO-t-Bu at xe2x88x9278xc2x0 C. Nevertheless, this synthetic enediyne was confirmed to exert the natural product-like biological activities in causing both DNA strand breakage and cell death [Nicolaou et al., J. Am. Chem. Soc., 110:4866 (1988); Nicolaou et al., J. Am. Chem. Soc., 114:7360 (1992)]. Jones and co-workers used an intramolecular carbenoid coupling reaction performed at xe2x88x9245xc2x0 C. in the presence of LiHMDS to close the 10-membered ring with significantly improved efficiency [Huber and Jones, Tetrahedron Lett., 35:2655 (1994); Jones et al., J. Chem.Soc., Chem. Commun., 1791 (1995)]. Beau and Crxc3xa9visy reported a synthesis of a 10-membered ring enediyne possessing a hydroxyl functionality by using the CrCl2xe2x80x94NiCl2-mediated ring closure as published in Tetrahedron Lett., 32:3171 (1991). However, the monocyclic enediynes are thermally unstable and readily undergo cycloaromatization at ambient temperature or above. The half-life of cyclodeca-1,5-diyn-3-ene was reported to be 18 hours at 37xc2x0 C. by Nicolaou et a. as published in J. Am. Chem. Soc., 110:4866 (1988). The thermal instability of the simple unsubstituted monocyclic enediynes therefore renders their practical application difficult.
Various 10-membered ring enediynes have been synthesised which are substituted at one or more of the four xe2x80x94CH2 positions between the two triple bonds, that is, the 7-, 8-, 9- and 10-positions. For instance, Suffert and Toussaint (Tetrahedron Lett., 38(31), 5507-5510, (1997)) disclose 10-membered ring enediynes which are substituted at the 7- and 8-positions and fused with a phenyl ring at the 9- and 10-positions and Dai et al (J. Org. Chem., 64,682-683, (1999)) discloses, inter-alia, (E)-3-hydroxy-4-benzylidene-10-anthraquinone-2-carbonyloxycyclodeca-1,5-diyne, 3-(1-hydroxy-1-phenyl)methyl-and 3-(1ethoxy-1-phenyl)methyl-7-anthraquinone-2-carbonyloxycyclodeca-1,5-diyn-3-ene.
It has now been discovered that certain novel C3-substituted cyclodeca-1,5-diyn-3-enes have improved thermal stability compared to the parent unsubstituted compound. Moreover, these compounds can be prepared from certain novel (E)-C3-substituted-4-(aryl- or heteroarylmethylidene)cyclodeca-1,5-diynes, which also have good thermal stability and act as enediyne prodrugs, by a novel method. Both the C3-substituted cyclodeca-1,5-diyn-3-enes and their precursors can be used as tools for interactions with DNA and proteins and as antimicrobial and antitumor agents.
According to a first aspect of the present invention there is therefore provided a compound having a nucleus of the general formula 
which may be substituted or, more preferably, unsubstituted, wherein
X represents a hydroxyl group or an optionally substituted alkoxy or acyloxy group; and
Y represents an optionally substituted aryl or heteroaryl group; or,
in the case of formula B, X and Y together with the interjacent carbon atom represent an optionally substituted heterocyclic group;
or a salt thereof. If a compound of formula (A) or (B) is substituted, it is preferred that the substituent or substituents is or are located at one or more of the 7-, 8-, 9- and 10-positions of the ring.
In a second aspect, a process for preparing compounds of the general formula A is provided which comprises either cyclizing an appropriate 10-halo-2-(aryl- or heteroarylmethylidene)deca-3,9-diyn-1-al in the presence of a first-row transition metal (II) halide, prefereably chromium (II) and/or nickel (II) chloride, or cyclizing a 2-halo- or 2-trifluoromethanesulfonate-1-(aryl- or heteroaryl)-3-(hydroxy- or alkoxy)undeca-1-en-4,10-diyne in the presence of a palladium (0) catalyst and a suitable co-catalyst, preferably copper (I) or silver (I) iodide, to form compounds of formula A in which X represents a hydroxyl group or an optionally substituted alkoxy group. If desired, compounds of formula A in which X represents a hydroxyl group can then be reacted with a suitable carboxylic acid, acid anhydride and/or acid chloride in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to form compounds of formula A in which X represents an optionally substituted acyloxy group.
In a third aspect, a process for preparing compounds of the general formula B is provided which comprises reacting a compound of the general formula A in which X represents an optionally substituted acyloxy group in the presence of a lanthanide catalyst to form compounds of the general formula B in which X represents an optionally substituted acyloxy group or X and Y together with the interjacent carbon atom represent an optionally substituted heterocyclic group.
In a fourth aspect, a process for preparing compounds of the general formula B is provided which comprises reacting a compound of the general formula A in which X represents a hydroxyl group with a protic acid in the presence of a suitable alcohol or with a protic acid optionally in the presence of water to form compounds of the general formula A in which X represents a hydroxyl group or an optionally substituted alkoxy group.
In another aspect, pharmaceutical compositions are provided which comprise a carrier and, as active ingredient, a compound of the general formula A or B or a salt thereof.
Methods for inhibiting tumor growth, treating cancer, inhibiting microbial growth, cleaving DNA and degrading or modulating a protein are also provided which utilize a compound of the general formula A or B or a salt thereof.